1. Field of the Invention
The present invention relates to novel ω-conotoxin peptides, more particularly, to novel ω-conotoxin peptides and its uses as well as methods for increasing the binding reversibility of a ω-conotoxin to N-type calcium channel.
2. Description of the Related Art
Cone snails represent a diverse family of marine mollusks that use venom for prey capture. The venom of each species contains a unique array of more than 100 peptides, whose pharmaceutical potential remain largely unexploited. Different classes of conotoxins have evolved to target ion channels and receptors for the successful capture of fish, mollusks, or worms [1-6].
One important class, the ω-conotoxins isolated from piscivorous species, inhibits neuronal voltage-sensitive calcium channels (VSCC) found in mammals. ω-Conotoxins have selectivity for N-type or P/Q-type VSCCs, making them widely used research tools for defining the distribution and role of neuronal VSCCs [7]. In addition to their use as research tools, animal studies have shown that ω-Conotoxins that target N-type VSCCs have clinical potential in ischemic brain injury and pain.
However, ω-Conotoxins presently available are not ideal therapeutics, despite their selectivity and potency and the dominant role of N-type VSCCs at synapses in carrying nociceptive information in the spinal cord.
For example, strong N-type VSCC selective blocker, GVIA, dissociates slowly from N-type VSCCs and, accordingly, may be difficult to administer in a clinical setting [8]. Another ω-Conotoxins MVIIA causes a variety of neurological side effects of unknown origin [9-11]. It was reported that MVIIA have more specificity on central N-type isoform than peripheral, although peripheral N-type isoform directly acting on pain signaling. CVID is more selective on the peripheral isoform than the central, therefore had fewer side effects than MVIIA [12-14]. Other ω-conotoxins are less selective for N-type VSCCs and are not considered useful therapeutic candidates.
On residue scanning experiments of N-type VSCCs blocker, Tyr13, Lys2, Arg10, Leu11, Arg21, N-term and C-term amide are important on affinity to channels [7, 15]. Recently, it has reported that Arg10 has also important role on reversibility of molecules. Substitution of Arg10 to Lys10 reduces reversibility significantly [14]. Although reversibility is closely correlated with affinity, dissociation of the two properties can be possible [16]. And the improvements on reversibility give potentials of better pain killer drug.
Throughout this application, various patents and publications are referenced and citations are provided in parentheses. The disclosure of these patents and publications in their entities are hereby incorporated by references into this application in order to more fully describe this invention and the state of the art to which this invention pertains.